Prior Heterologous Flavivirus Exposure Results in Reduced Pathogenesis in a Mouse Model of Zika Virus Infection.
Prior Heterologous Flavivirus Exposure Results in Reduced Pathogenesis in a Mouse Model of Zika Virus Infection.
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DOI：
10.1128/jvi.00573-21
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发表时间：
2021-07-26
影响因子：
5.4
通讯作者：
Pinto AK
中科院分区：
文献类型：
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作者：
Hassert M;Steffen TL;Scroggins S;Coleman AK;Shacham E;Brien JD;Pinto AK
2015/2016年寨卡病毒在南美洲和中美洲的流行让科学界迫切地试图了解导致寨卡病毒发病的因素。由于多种其他黄病毒在寨卡病毒出现的地区流行，因此假设了解寨卡病毒疾病严重程度的关键是在先前黄病毒暴露的背景下研究寨卡病毒感染。人类和动物研究强调了先前暴露于不同黄病毒的想法可能会调节对寨卡病毒的免疫反应。然而，目前尚不清楚先前的黄病毒暴露如何影响寨卡病毒负担和疾病。在这项小鼠研究中，我们纵向研究了寨卡病涉及的多种因素，将病毒负荷与神经系统疾病严重程度增加，体重减轻和炎症联系起来。我们表明，先前与登革热病毒2型或3型或黄热病疫苗株接触的异源黄病毒在致命的寨卡病毒攻击中提供了死亡保护。然而，病毒负荷和寨卡病的减少取决于感染的原发性黄病毒;原发性寨卡病毒感染对寨卡病毒攻击最具保护性，其次是登革热病毒2，黄热病和登革热病毒3保护免于死亡，但显示出更严重的疾病。本研究证明了先前黄病毒暴露对寨卡病毒发病机制的保护作用的变化，并确定了原发性黄病毒感染与寨卡病毒病的可能性之间的独特关系。重要性近年来，各种病媒传播疾病的出现和重新出现突出了了解每种病原体的保护机制的必要性。在这项研究中，我们调查了先前暴露于寨卡病毒，登革热病毒血清型2或3，或黄热病疫苗株对寨卡病毒感染小鼠模型的发病机制和疾病结果的影响。我们发现，先前暴露于异源黄病毒可保护免于死亡，并且在不同程度上，先前的黄病毒暴露可在致命的寨卡病毒攻击期间保护免于神经系统疾病，体重减轻和严重的病毒负荷。使用纵向和横断面研究设计，我们能够将多个疾病参数（包括病毒负荷）与黄病毒感染背景下的神经系统疾病严重程度、体重减轻和炎症反应联系起来。本研究证明了既往黄病毒暴露对调节黄病毒病理生理学的可测量但不同的影响。鉴于大多数黄病毒暴发的周期性，这项工作将有助于预测未来暴发的疾病严重程度。
The 2015/2016 Zika virus epidemic in South and Central America left the scientific community urgently trying to understand the factors that contribute to Zika virus pathogenesis. Because multiple other flaviviruses are endemic in areas where Zika virus emerged, it is hypothesized that a key to understanding Zika virus disease severity is to study Zika virus infection in the context of prior flavivirus exposure. Human and animal studies have highlighted the idea that having been previously exposed to a different flavivirus may modulate the immune response to Zika virus. However, it is still unclear how prior flavivirus exposure impacts Zika viral burden and disease. In this murine study, we longitudinally examine multiple factors involved in Zika disease, linking viral burden with increased neurological disease severity, weight loss, and inflammation. We show that prior heterologous flavivirus exposure with dengue virus type 2 or 3 or the vaccine strain of yellow fever provides protection from mortality in a lethal Zika virus challenge. However, reduction in viral burden and Zika disease varies depending on the infecting primary flavivirus; with primary Zika virus infection being most protective from Zika virus challenge, followed by dengue virus 2, with yellow fever and dengue virus 3 protecting against mortality but showing more severe disease. This study demonstrates the variation in protective effects of prior flavivirus exposure on Zika virus pathogenesis and identifies distinct relationships between primary flavivirus infection and the potential for Zika virus disease. IMPORTANCE The emergence and reemergence of various vector-borne diseases in recent years highlights the need to understand the mechanisms of protection for each pathogen. In this study, we investigated the impact of prior exposure to Zika virus, dengue virus serotypes 2 or 3, or the vaccine strain of yellow fever on pathogenesis and disease outcomes in a mouse model of Zika virus infection. We found that prior exposure to a heterologous flavivirus was protective from mortality, and to varying degrees, prior flavivirus exposure was protective against neurological disease, weight loss, and severe viral burden during a lethal Zika challenge. Using a longitudinal and cross-sectional study design, we were able to link multiple disease parameters, including viral burden, with neurological disease severity, weight loss, and inflammatory response in the context of flavivirus infection. This study demonstrates a measurable but varied impact of prior flavivirus exposure in modulating flavivirus pathophysiology. Given the cyclic nature of most flavivirus outbreaks, this work will contribute to the forecasting of disease severity for future outbreaks.